The efficacy of treatments for many diseases, including cancer, has improved dramatically in the past few decades, however, many treatment regimens require the use of drugs with deleterious side effects, including, for example, alopecia, nausea, vomiting, tiredness, etc. Some treatment regimens may also entail the use of drugs that are not stable under physiological conditions, for example, bio-therapeutics (e.g., genes or gene products) and/or other drugs that are easily degraded or otherwise altered upon administration and thereby loose their effectiveness before achieving the desired therapeutic result. Such instability also makes the drugs more difficult and costly to store and prepare for administration.
There are a number of classes of anticancer agents, encompassing nearly 100 individual drugs, as well as numerous drug combination therapies, methods of delivery and treatment regimens. Anticancer agents may be classified according to several criteria, such as class of compound and disease state treated. Certain agents have been developed to take advantage of the rapid division of cancer cells and target specific phases in the cell cycle, providing another method of classification. Agents can also be grouped according to the type and severity of their side effects or method of delivery. However, the most common classification of non-biotherapeutic based anticancer agents is by class of chemical compound, which broadly encompasses the mechanism of action of these compounds.
Depending on the reference source consulted, there are slight differences in the classification of anticancer agents. The classes of compounds are described in the Physician's Desk Reference as follows: alkaloids; alkylating agents; anti-tumor antibiotics; antimetabolites; hormones and hormone analogs; immunomodulators; photosensitizing agents; and miscellaneous other agents.
The alkaloid class of compounds may also be referred to as mitotic inhibitors, as they are cell cycle phase specific and serve to inhibit mitosis or inhibit the enzymes required for mitosis. They are derived generally from plant alkaloids and other natural products and work during the M-phase of the cell cycle. This class of compounds is often used to treat neoplasias such as acute lymphoblastic leukemia, Hodgkin's and non-Hodgkin's lymphoma; neuroblastomas and cancers of the lung, breast and testes.
Alkylating agents make up a large class of chemotherapeutic agents, including of the following sub-classes, which each represent a number of individual drugs: alkyl sulfonates; aziridines; ethylenimines and methylmelamines; nitrogen mustards; nitrosoureas; and others, including platinum compounds. Alkylating agents attack neoplastic cells by directly alkylating the DNA of cells and therefore causing the DNA to be replication incompetent. This class of compounds is commonly used to treat a variety of diseases, including chronic leukemias, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma and certain lung, breast and ovarian cancers.
Nitrosoureas are often categorized as alkylating agents, and have a similar mechanism of action, but instead of directly alkylating DNA, they inhibit DNA repair enzymes causing replication failure. These compounds have the advantage of being able to cross the blood-brain barrier and therefore can be used to treat brain tumors.
Antitumor antibiotics have antimicrobial and cytotoxic activity and also interfere with DNA by chemically inhibiting enzymes and mitosis or by altering cell membranes. They are not cell cycle phase specific and are widely used to treat a variety of cancers.
The antimetabolite class of anticancer agents interfere with the growth of DNA and RNA and are specific to the S-phase of the cell-cycle. They can be broken down further by type of compound, which include folic acid analogs, purine analogs, and pyrimidine analogs. They are often employed in the treatment of chronic leukemia, breast, ovary, and gastrointestinal tumors.
There are two classes of hormones or hormone analogs used as anticancer agents, the corticosteroid hormones and sex hormones. While some corticosteroid hormones can both kill cancer cells and slow the growth of tumors, and are used in the treatment of lymphoma, leukemias, etc., sex hormones function primarily to slow the growth of breast, prostate and endometrial cancers. There are numerous subclasses of hormones and hormone analogs, including, androgens, antiadrenals, antiandrogens, antiestrogens, aromatase inhibitors, estrogens, leutenizing hormone releasing hormone (LHRH) analogs and progestins.
An additional smaller class of anticancer agents is classified as immunotherapy. These are agents that are intended to stimulate the immune system to more effectively attack the neoplastic (cancerous) cells. This therapy is often used in combination with other therapies.
There are also a number of compounds, such as campothectins, which are generally listed as ‘other’ anticancer agents and can be used to treat a variety of neoplasias.
Combinations of anticancer agents are also utilized in the treatment of a number of cancers. For example, Sanofi Syntholabo markets ELOXATIN™ (oxaliplatin for injection) for the treatment of colorectal cancer for use in combination with 5-fluorouracil and leuvocorin. This combination of drugs is often used adjunctively with surgery in the treatment of colorectal cancer. Oxaliplatin is an alkylating agent that is believed to act by inhibiting both DNA replication and transcription. Unlike other platinum agents, oxaliplatin has demonstrated a decreased likelihood of resistance development. Oxaliplatin is further described in U.S. Pat. Nos. 4,169,846; 5,338,874; 5,298,642; 5,959,133; 5,420,319; 5,716,988; 5,290,961; and in Wilkes G M. “New therapeutic options in colon cancer: focus on oxaliplatin” Clin J Oncol Nurs. (2002) 6:131-137.
While there are a plethora of anticancer agents, the benefit of these compounds is often outweighed by the severity of the side effects produced by the agent. This comparison is often referred to as the therapeutic index, which describes the balance between the required dose to accomplish the destruction of the cancer cells compared to the dose at which the substance is unacceptably toxic to the individual. The drawback to most anticancer agents is the relatively small range of the therapeutic index, (i.e., the narrow dosage range in which cancer cells are destroyed without unacceptable toxicity to the individual). This characteristic limits the frequency and dosage where an agent is useful, and often the side effects become intolerable before the cancer can be fully eradicated.
The severe side effects experienced with the majority of cancer chemotherapeutics are a result of the non-specific nature of these drugs, which do not distinguish between healthy and cancerous cells, and instead destroy both. Certain cell cycle specific drugs attempt to lessen these effects, targeting phases of the cell cycle involved in cell replication and division. These drugs do not, however, distinguish between cancerous cells and healthy cells that are undergoing normal cell division. The cells most at risk from these types of chemotherapy are those which undergo cell division often, including blood cells, hair follicle cells, and cells of the reproductive and digestive tracts.
The most common side effects of anticancer agents are nausea and vomiting. A large proportion of individuals also suffer from myelosuppression, or suppression of the bone marrow, which produces red blood cells, white blood cells and platelets. These and other side effects are also exacerbated by the suppression of the immune system concomitant with the destruction and lack of production of white blood cells, and associated risk of opportunistic infection.
Other side effects common to a wide range of anticancer agents include: hair loss (alopecia); appetite loss; weight loss; taste changes; stomatitis and esophagitis (inflammation and sores); constipation; diarrhea; fatigue; heart damage; nervous system changes; lung damage; reproductive tissue damage; liver damage; kidney and urinary system damage.
The wide range of the side effects associated with most anticancer agents and their severity in individuals who are already debilitated with disease and possibly immune compromised has led researchers to search for mechanisms by which they can alleviate some of the side effects while maintaining the efficacy of the treatment. Several approaches to this problem have been taken. They include combination chemotherapy, where multiple anticancer agents are administered together; adjuvant therapies, where additional agents are prescribed along with the anticancer agent to fight the side effects of the anticancer agent; combined modality treatments, where chemotherapy is combined with radiation and/or surgery; and alternative delivery vehicles for the administration of anticancer agents, such as the encapsulation of anticancer agents in liposomes.
Liposomes are formed when phospholipids and their derivatives are dispersed in water. Upon dispersion in water the phospholipids form closed vesicles called “liposomes”, which are characterized by lipid bilayers encapsulating an aqueous core. Various liposomes have been used as carriers for entrapped therapeutic agents, such as drugs, enzymes and genetic sequences for use in medical science, in pharmaceutical science and in biochemistry.
Examples of liposome compositions include U.S. Pat. Nos. 4,983,397; 6,476,068; 5,834,012; 5,756,069; 6,387,397; 5,534,241; 4,789,633; 4,925,661; 6,153,596; 6,057,299; 5,648,478; 6,723,338; 6,627218; U.S. Pat. App. Publication Nos: 2003/0224037; 2004/0022842; 2001/0033860; 2003/0072794; 2003/0082228; 2003/0212031; 2003/0203865; 2004/0142025; 2004/0071768; International Patent Applications WO 00/74646; WO 96/13250; WO 98/33481; Papahadjopolulos D, Allen T M, Gbizon A, et al. “Sterically stabilized liposomes. Improvements in pharmacokinetics and antitumor therapeutic efficacy” Proc Natl Acad Sci U.S.A. (1991) 88: 11460-11464; Allen T M, Martin F J. “Advantages of liposomal delivery systems for anthracyclines” Semin Oncol (2004) 31: 5-15 (suppl 13). Weissig et al. Pharm. Res. (1998) 15: 1552-1556.
In earlier stages of developing liposomes, naturally occurring phospholipids of the cell membrane such as egg-yolk phospholipids and soybean phospholipids were used. In the case of being intravenously administered, however, liposomes utilizing these phospholipids are likely to be incorporated into the reticuloendothelial system of liver or spleen, causing a problem of low blood retention time and thereby reducing the efficacy of the drug. Thereafter, as a means for solving this problem, synthetic phospholipids whose lipid portion contains only saturated bonds were used as a constituent of the liposome membrane in order to harden the liposome membrane.
In an effort to prolong the circulatory half-life of liposomes and avoid uptake by the reticuloendothelial system, researchers developed liposomes that were modified by the incorporation of polyethylene glycol or other hydrophilic polymers (e.g., a PEG liposome where one or more of the constituent lipids was modified by attachment of PEG). PEG-modified liposomes were also often referred to as “shielded” liposomes. Doxil™ (doxorubicin HCl liposome injection) is a liposome-enclosed doxorubicin, with adjunct polyethylene glycol (PEG) utilized to avoid the reticuloendothelial system (RES) and prolong drug circulation time. See Vail D M, Amantea M A, Colbern G T, et al., “Pegylated Liposomal Doxorubicin. Proof of Principle Using Preclinical Animal Models and Pharmacokinetic Studies.” Semin Oncol. (2004) 31 (Suppl 13): 16-35. However, adverse effects were also caused by prolonged blood retention (e.g., hand-foot syndrome, an adverse effect of Doxil® on the peripheral system, etc.) became recognized as a problem.
Examples of liposomes include U.S. Pat. Nos. 4,983,397; 5,013,556; 6,316,024; 6,056,973; 5,945,122; 5,891,468; 6,126,966; 5,593,622, 5,676,971; 6,586,559; and 5,846,458 U.S. Pat. App. Publication. Nos. 2003/0224037; 2004/0022842; 2003/0113262; 2002/0136707; International Patent Applications WO 99/30686; WO 02/41870 Alimiñana et al., Prep. Biochem. Biotech. (2004) 34(1): 77-96. Liposomes are also described in U.S. Pat. Nos. 6,228,391; 6,197,333; 6,046,225; 5,292,524; and U.S. Pat. App. Pub. Nos. 20050271588; 20040213833; 20040029210; 20030175205; 20030162748; 20030130190; 20030059461; and 20020034537.
In addition to PEG-modified liposomes, researchers developed a variety of other derivatized lipids. These derivatized lipids could also be incorporated into liposomes. See, for example: International Patent Application WO 93/01828; Park Y S, Maruyama K, Huang L. “Some negatively charged phospholipids derivatives prolong the liposome circulation in vivo.” Biochimica et Biophysica Acta (1992) 1108: 257-260; Ahl et al., Biochimica Biophys. Acta (1997) 1329: 370-382.
Additional lipid compositions are described in U.S. Pat. Nos. 6,936,272; 6,897,196; 6,077,834; and U.S. Pat. App. Pub. Nos. 20050136064; 20040234588; 20030215490; 20030166601; and 20010038851.
In addition to modification of liposomes with PEG and other hydrophilic polymers, researchers also developed liposomes that aimed to specifically target particular cell types by incorporating targeting factors (also referred to as targeting ligands) for particular cell types. Examples of targeting factors/ligands include asialoglycoprotein, folate, transferrin, antibodies, etc. In some cases one or more of the constituent lipids could be modified by the attachment of a targeting factor.
Examples of lipid compositions including targeting factors include U.S. Pat. Nos. 5,049,390; 5,780,052; 5,786,214; 6,316,024; 6,056,973; 6,245,427; 6,524,613; 6,749,863; 6,177,059; 6,530,944; U.S. Pat. App. Publication. Nos. 2004/0022842; 2003/0224037; 2003/143742; 2003/0228285; 2002/0198164; 2003/0220284; 2003/0165934; 2003/0027779; International Patent Application Nos. WO 95/33841; WO 95/19434; WO 2001037807; WO 96/33698; WO 2001/49266; WO 9940789; WO 9925320; WO 9104014; WO 92/07959; EP 1369132; JP 2001002592; Iinuma H, Maruyama K, et al., “Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer” Int J Cancer (2002) 99 130-137; Ishida 0, Maruyama K, Tanahashi H, Iwatsuru M, Sasaki K, et al., “Liposomes bearing polyethylene glycol-coupled transferrin with intracellular targeting property to the solid tumors in vivo.” Pharmaceutical Research (2001) 18: 1042-1048; Holmberg et al., Biochem. Biophys. Res. Comm. (1989) 165(3):1272-1278; Nam et al., J. Biochem. Mol. Biol. (1998) 31(1): 95-100; Nag et al., J. Drug Target. (1999) 6(6): 427-438.
In particular, Iinuma et al. developed a Tf-PEG-liposome, with transferrin (Tf) attached at the surface of the liposome. Iinuma et al., showed that a greater number of liposomes were bound to the surface of the tumor cells, and there was a greater uptake of liposomes by the tumor cells for Tf-PEG-liposome as compared to PEG-liposome (Inuma et al., ibid; Ishida et al., ibid).
However, despite recent advances made in the drug and labeled compound delivery field, including the use of liposome compositions, there is still a need for improved liposome compositions for the delivery of drugs and labeled compounds to specific cells and/or tissues that achieve a therapeutic or diagnostic effect. In particular in the cancer field, drug formulations with improved specificity and reduced toxicity are need to ensure therapeutic benefit without adversely effecting healthy cells and which also do not result in deleterious side effects for the individual being treated. Similarly, labeled compounds that can be used to detect conditions, particularly life-threatening conditions at an early stage (e.g., with high specificity and/or high sensitivity) and also accurately monitor the severity/extent of the condition (e.g., progression and/or regression with or without treatment) would also significantly improve the quality and success of therapy.